tbuckley/cabot-search huggingface dataset:
EXTH-29. RADIOSENSITIZATION BY BRD4 INHIBITION IN DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Jun Watanabe, Matt Clutter, Amreena Suri, Koki Abe, Yukitomo Ishi, Oren Becher, Rintaro Hashizume
Journal: Neuro-Oncology (2022)

Abstract Diffuse intrinsic pontine glioma (DIPG), the most frequent brainstem tumor in pediatrics, is one of the devastating childhood cancers, and virtually all patients die within two years after diagnosis. Since these tumors occur in the brainstem which is vital area, there are no surgical options for providing relief to patients, and conventional chemotherapy. Radiation therapy (RT) remains the only effective treatment. Radiosensitization is a mean to improve the therapeutic balance between efficacy and toxicity of RT, but not used in clinically. Here, we found BRD4 inhibitor as a radiosensitizer from drug screening. DIPG shows increased H3 K27 acetylation (H3K27ac), which binds to BET bromodomain protein 4 (BRD4) and they are strongly associated with active transcription. We tested two BRD4 inhibiter (BRD4i : AZD5153 and JQ-1) and genetic BRD4 depletion enhances radiation-induced DNA damage, making it a potential radiosensitizer in the treatment of DIPG. We evaluated the effects of BRD4i on genes expression using RNA sequence, inhibited significantly DNA-repair proteins such as BRCA1 and RAD51. CUT-RUN qPCR showed decreased H3K27ac at BRCA1 and RAD51. Combination with BRD4i and RT inhibited cell viability significantly in clonogenic survival assay, apoptosis assay, and showed cell cycle arrest. Radiation-induced DNA double-strand break (DSB) repair was prolonged high level of rH2AHX and 53BP1 with BRD4i because of inhibited DNA-repair. In vivo studies revealed increased survival of animals treated with combination therapy of RT and BRD4i in compared to either monotherapy. Together, these results highlight BRD4i as a potential radiosensitizer and provide a rationale for developing combination therapy with radiation in the treatment of DIPG.
INNV-01. DRAMATIC RESPONSE OF ERBB2 POSITIVE BRAIN METASTASES FROM LUNG ADENOCARCINOMA TO FAM-TRASTUZUMAB DERUXTECAN-NXKI
Authors: Tracy Thompson, Sara Luster, Panayiotis Savvides, Terence Sio, Lynsey Westerlund, Shannon Fortin-Ensign, Maciej Mrugala
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND In May 2022 the Food and Drug Administration approved fam-trastuzumab deruxtecan-nxki (FAM-TRAS) for adult patients with unresectable or metastatic Her-2 positive breast cancer who have received prior Her-2-based regimen and developed recurrence withing 6 months of completing therapy. Efficacy of the drug was established in the DESTINY-BreastO3 study. It has been suggested that fam-trastuzumab deruxtecan crosses blood-brain barrier, similarly to trastuzumab and another drug conjugate trastuzumab-DM1. CNS responses in patients with Her2 positive metastatic breast cancer have been reported. ERBB2 is a receptor tyrosine kinase from the family of EGFR/ERBB/HER family of kinases and its alterations can serve as a biomarker and actionable target in solid tumors. Here we present a case of CNS metastases from ERBB2 positive lung adenocarcinoma treated successfully with FAM-TRAS alone. METHODS Case report. RESULTS 50 y old man presented with a persistent cough. CT chest showed RUL nodule and peribronchial lymphadenopathy. Biopsy was positive for adenocarcinoma. Molecular testing has shown ERBB2 exon20 insertion, TP53 pathogenic variant, PDL1 positive (1%), and BRACA1 mutation. The patient had a solitary brain metastasis at the time of the initial diagnosis. He was started on FAM-TRAS and CNS response was seen while lung disease progressed. He was switched to immunotherapy but developed pneumonitis and therapy was stopped. He subsequently developed innumerable brain metastases and was restarted on FAM-TRAS. After 2 doses, dramatic response in CNS was seen with lung disease was stable. CONCLUSIONS This case demonstrates the critical importance of molecular testing in neuro-oncology in the era of novel systemic therapies, many with good blood-brain barrier penetration. Systemic therapies for brain metastases can be successfully implemented in the right clinical setting and they can allow for the deferral of radiotherapy. ERBB2 mutations can guide clinicians when choosing therapy for many solid tumors, including those with brain metastases.
TMET-13. SEX DIFFERENCES IN GLUCOSE METABOLISM AND MITOCHONDRIAL FUNCTION IN GLIOBLASTOMA IMPLICATE HYPOXIA-INDUCIBLE FACTOR 1 ALPHA (HIF1A) ACTIVITY
Authors: Jianyun Lu, Jasmin Sponagel, Jill Jones, Hannah Gass, Elena Nunez, Cheryl Frankfater, Sierra Williams-McLeod, Camryn Marquez, Prakash Chinnaiyan, Joshua Rubin, Joseph Ippolito
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. It is more prevalent in males and female patients have better survival. Investigating the molecular mechanisms underlying this disparity is imperative for understanding its development and progression as well as developing novel treatment paradigms. Carbohydrate (namely glucose) metabolism is a critical GBM nutrient source for biosynthesis, energetics, and reducing equivalents. Previously, our group discovered that elevated glycolytic activity uniquely predicted the outcomes of male, but not female, lower grade glioma patients. Our goal was to characterize sex differences in GBM carbohydrate metabolism and their effects on cellular phenotype. First, we discovered that male transformed murine astrocytes were more susceptible to glucose deprivation than females. We confirmed this phenotype with irreversible inhibition of hexokinase with 2-deoxyglucose as well as a GLUT1-selective inhibitor. Time-resolved stable isotope tracing of cell metabolism with carbon-13 glucose in transformed astrocytes further supported these findings; male cells had significantly higher rates of glucose uptake and metabolism than female cells. These results were validated with stable isotope metabolomics datasets from human cancer cell lines. Using additional assays of cellular metabolism, we discovered that male transformed astrocytes had a higher glycolytic rate, higher pyruvate kinase activity, higher mitochondrial respiration, and higher mitochondrial mass compared to females. This was validated by a TCGA pancancer analysis that revealed significantly higher expression of nuclear genes involved in mitochondrial regulation in males than in females. This prompted us to identify possible regulators of this metabolic phenotype. We discovered that HIF1A had robust hypoxia-inducible expression that was significantly higher in male transformed astrocytes. Moreover, HIF1A expression as well as its target transcripts were significantly higher in TCGA pancancer tumor datasets. Together, our data underscore the potential for developing sex-specific metabolic targeting approaches for patients with GBM.
BIOM-57. DISSECTING STEMNESS IN AGGRESSIVE MENINGIOMAS: PROGNOSTIC ROLE OF SOX2 EXPRESSION
Authors: Rina Di Bonaventura, Maurizio Martini, Tonia Cenci, Valerio Maria Caccavella, Valeria Barresi, Marco Gessi, Alessio Albanese, Liverana Lauretti, Roberto Pallini, Quintino Giorgio D'Alessandris, Alessandro Olivi
Journal: Neuro-Oncology (2022)

Abstract Aggressive meningiomas are prone to recur despite GTR and eventually progress: they represent a challenge and are difficult to recognize at first diagnosis. SOX2 (Sex-determining region Y-box2) is a transcription regulator whose role is crucial for cell’s fate and maintenance of progenitor’s identity during embryogenesis, and homeostasis and regeneration in adult tissue through stem cell activity preservation. We reviewed meningioma cases surgically treated at Gemelli Hospital, Rome between 2014 and 2019. We included all patients with diagnosis of grade 3 meningiomas, both progressive and de novo, grade 2 with at least one surgical recurrence after GTR and benign grade 1 and grade 2 without recurrence at 10 and 5 years long follow-up respectively. SOX2 expression was evaluated through IHC and RT-PCR. Its role in predicting progression, recurrence, OS and PFS was investigated. 87 patients were included: 16 de novo grade 3 meningioma, 7 progressive grade 1, 13 progressive grade 2, 12 recurrent grade 2, 20 benign grade 1, 19 benign grade 2. The IHC method for SOX2 was validated by correlation between IHC score and mRNA levels (Spearman R=0.0398, p=0.001, AUC 0.87). Although SOX2 expression is related to WHO grade in the series, its status doesn’t change with progression. SOX2 expression at first surgery is related to risk of progression (p&amp;lt; 0,0001) and represents a grade independent prognostic factor for PFS and OS (PFS 38,41 months in positive cases vs not reached in negative cases; p&amp;lt; 0,0001; OS 173,9 months in positive cases vs not reached in negative cases; p=0,0001) and both in grade 1 and grade 2. Histomorphological criteria, cornerstone of the current WHO classification, are inadequate to predict aggressiveness. SOX2 expression since first diagnosis is able to point out meningiomas prone to recur and progress. SOX2 status could integrate current classification as molecular biomarker of stemness and aggressiveness.
CTIM-12. A PHASE I CLINICAL TRIAL ON THE INTRACRANIAL ADMINISTRATION OF INCREASING DOSES OF IPILIMUMAB PLUS FIXED DOSE NIVOLUMAB IN PATIENTS WITH RECURRENT GLIOBLASTOMA (RGB)
Authors: Wietse Geens, Julia Katharina Schwarze, Jens Tijtgat, Louise Lescrauwaet, Sandra Tuyaerts, Xenia Geeraerts, Latoya Stevens, Anne-Marie Vanbinst, Hendrik Everaert, Michaël Bruneau, Johnny Duerinck, Bart Neyns
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Intra-operative intracerebral (iCE) administration of ipilimumab (IPI) and nivolumab (NIVO) after resection of rGB is safe and resulted in encouraging survival (NCT03233152J; Duerinck et al. JITC 2021). METHODS Eligible patients (pts) underwent a maximal safe resection followed by iCE administration of 5 mg IPI plus 10 mg NIVO and implantation of an Ommaya reservoir through which NIVO (10 mg) and IPI (cohort defined doses of 1-, 5- and 10 mg of IPI) were administered intracavitary (iCA) in combination with NIVO (10 mg) intravenously pre- and postoperatively and Q2w thereafter for up to 24w. RESULTS 20 pts (13 male; median age 58y) were enrolled. One patient was excluded due to an intra-operatively diagnosed epidural bacterial infection. Respectively 4 pts were treated at the 1-, 4 pts at the 5-, and 11 pts at the 10 mg iCA IPI dose level. Median number and range of postoperative iCA administrations of IPI/NIVO was 2 (0-4) at the 1 mg dose level, 5 (1-10) at the 5 mg dose level, and pending for the 10 mg dose level. Most important treatment related adverse events were symptomatic aseptic neutrophilic pleocytosis (3 pts, all treated at the 10 mg IPI dose level), subacute cerebral edema necessitating corticosteroid treatment (5 pts), and bacterial colonization of the Ommaya reservoir (3 pts). There were no G5 AE. Nine pts have progressed and 4 pts died from progressive disease. Molecular-genetic characterization of rGB tissues, analysis of cellular and cytokine content, and NIVO/IPI concentrations in CSV samples are ongoing. CONCLUSION Repeated iCA administration of 10 mg NIVO plus 10 mg IPI resulted in treatment limiting aseptic neutrophilic pleocytosis. Safety of the presumed MTD of repeated 10 mg NIVO plus 5 mg IPI iCA will be further investigated.
RBIO-06. CLINICAL AND MOLECULAR PREDICTORS OF RADIATION RESPONSIVENESS IN MENINGIOMAS: A MULTICENTER RETROSPECTIVE COHORT STUDY
Authors: Justin Wang, Farshad Nassiri, Vikas Patil, Jeff Liu, Grace Lee, Lauren Rogers, Derek Tsang, Normand Laperriere, Gelareh Zadeh
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Aside from surgery, radiotherapy (RT) remains the only standard of care treatment for meningiomas. However, few studies have identified clinical/molecular biomarkers associated with responsiveness to RT and the optimal timing of RT after surgery remains controversial. We aimed to assess outcomes in a large multi-institutional cohort of RT-treated meningiomas to identify clinical factors and DNA methylation and RNA expression markers associated with progression-free survival (PFS) post-RT. METHODS Patients with intracranial meningiomas who underwent treatment with fractionated RT between 1997-2018 were included. DNA-methylation using the Illumina 850K EPICArray and RNA-sequencing were performed on tumours with sufficient tissue. Primary endpoints were radiographic recurrence of progression and time to progression from the time of RT completion. RESULTS 404 meningiomas were included for analysis. Of these, 167 (41.3%) recurred post-RT, usually within 5-years of RT. Previous RT to the meningioma, having a WHO grade 3 meningioma, and older age at diagnosis were independently associated with poorer PFS post-RT. Following propensity score matching, patients that received adjuvant RT had significantly better PFS post-RT compared to those that received salvage RT after recurrence (p=0.04). DNA methylation on 220 of these meningiomas segregated tumours into two distinct methylation groups (RT-resistant and RT-sensitive) based on unsupervised consensus clustering. DNA methylation were able to independently predict PFS post-RT better than all clinical factors. Differential RNA-expression analysis of these groups showed up-regulation of pathways involved in chromosome segregation and mitotic cell cycle and down-regulation of fatty acid metabolism pathways in RT-resistant meningiomas. CONCLUSION While there are a paucity of clinical factors that can reliably predict a meningioma’s response to RT, DNA methylation and RNA expression biomarkers may aid in differentiating RT-resistant meningiomas from RT-sensitive tumours. Patients that receive adjuvant RT may have prolonged PFS post-RT compared to those that receive salvage RT only after recurrence has already occurred.
TMET-34. RADIATION METABOLOMICS IN PRIMARY HUMAN MENINGIOMA AND SCHWANNOMA: EARLY EXPERIENCE AND INITIAL RESULTS
Authors: Mark Dougherty, Eric Taylor, Marlan Hansen
Journal: Neuro-Oncology (2022)

Abstract Introduction Meningiomas and schwannomas account for 45% of primary CNS tumors. Yet when surgery and radiation fail, no further treatments exist. Metabolomics has been used to discover new cancer therapies; however, to date few have used metabolomics to study meningiomas and schwannomas. Here we present initial results and lessons learned from this novel endeavor. METHODS Primary tumors were obtained from patients during surgery and immediately taken for culturing or xenograft implantation. Upon reaching &amp;gt;90% confluence, cultures were treated with 0gy, 3gy, 10gy, or 20gy gamma radiation, then flash frozen 6 or 72 hours post-treatment. Xenograft tumors were implanted in nude mice. MRI 4 weeks post-implantation confirmed tumor viability. Mice were then given 10gy, 20gy, or sham radiation treatment. Xenografts were harvested 72 hours post-treatment. Metabolites were measured with a ThermoISQ gas chromatography-mass spectrometer. RESULTS Eleven meningiomas and nine schwannomas were successfully cultured. Unsupervised hierarchical clustering of cultures demonstrated greater influence from tumor of origin than from radiation. Univariate analysis of schwannoma xenografts demonstrated elevated ornithine following radiation (fold change 1.62; P = 0.008). However, principal component analysis did not show significant between-group differentiation. Orthotopic meningioma xenografts did not produce sufficient tissue for metabolomics; however, subsequent subcutaneous implants have been successful (data forthcoming). CONCLUSION Standard cell cultures did not reveal significant metabolic changes following radiation; it is unclear whether this was due to culture technique or inter-tumor heterogeneity. In radiated schwannoma xenografts, elevated ornithine may implicate related pathways such as ornithine decarboxylase-mediated polyamide synthesis for DNA double-strand break repair. Compared to other ‘-omics’ studies, metabolomics requires more tissue per sample ( &amp;gt;10mg) and is more sensitive to environmental conditions. Thus, large sample sizes are needed to detect significant changes, and xenografts are likely superior to cell culture. Future plans include increased xenograft sample size and stable isotope tracing for pathway analysis.
CNSC-06. TEMOZOLOMIDE-INDUCED GUANINE MUTATIONS CREATE EXPLOITABLE VULNERABILITIES OF GUANINE-RICH DNA AND RNA REGIONS IN DRUG-RESISTANT GLIOMAS
Authors: Deanna Tiek, Shi-Yuan Cheng, Xiao Song, Anshika Goenka, Rebeca Iglesia, Bo Hu, Rebecca Riggins
Journal: Neuro-Oncology (2022)

Abstract Temozolomide (TMZ) is a chemotherapeutic agent that has been the first-line standard of care for the aggressive braincancer glioblastoma (GBM) since 2005. Although initially beneficial, TMZ resistance is universal and second-lineinterventions are an unmet clinical need. Here, we took advantage of the known mechanism of action of TMZ to targetguanines (G) and investigated G-rich G-quadruplex (G4) and splice site changes that occur upon TMZ resistance. We reportthat TMZ-resistant GBM has guanine mutations that disrupt the G-rich DNA G4s and splice sites that lead to deregulatedalternative splicing. These alterations create vulnerabilities, which are selectively targeted by either the G4-stabilizingdrug TMPyP4 or a novel splicing kinase inhibitor of cdc2-like kinase. Lastly, we show that the G4 and RNA binding proteinEWSR1, member of the FUS, EWSR1, and TAF15 family, aggregates in the cytoplasm in TMZ-resistant GBM cells and patient samples. Together, our findings provide insight into targetable vulnerabilities of TMZ-resistant GBM and present cytoplasmic EWSR1 as a putative biomarker.
NCOG-06. CASE REPORT: EXTENDED REMISSION OF HER2-POSITIVE BREAST CARCINOMA WITH BRAIN METASTASES AND LEPTOMENINGEAL DISEASE FOLLOWING INTRATHECAL AND SYSTEMIC TRASTUZUMAB
Authors: Timothy Gregory, Monica Loghin
Journal: Neuro-Oncology (2022)

Abstract Leptomeningeal disease (LMD) in breast cancer carries a poor prognosis with median overall survival (OS) of 3-4 months. Recent series have indicated prolongation of OS up to 10-13 months in HER2-positive breast LMD treated with intrathecal (IT) trastuzumab. Here we present an unprecedented long-term survival with clinical, radiographic, and molecular response for more than 10 years on IT trastuzumab. A 52-year-old woman presented in 12/2011 with newly diagnosed LMD with previously treated brain and systemic metastases. Her initial diagnosis of HER2-positive left intraductal carcinoma in 5/2005 was treated with bilateral mastectomy, adjuvant chemotherapy with doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab, as well as local RT. She was disease free until 10/2009 when she presented with headache due to two brain metastases involving the vermis and right occipital lobe. She underwent resection and SRS, followed by chemotherapy with capecitabine and lapatinib. In 12/2010 she received further RT to the posterior fossa for recurrent disease and later required gamma knife to a left occipital metastasis. In 8/2011 she developed back pain and cauda equina syndrome. MRI spine revealed LMD from T11- L2. CSF studies showed &amp;gt; 500 protein, 17 WBCs and malignant cells consistent with her breast primary. Both cerebellar metastasis and cells in the spinal fluid showed over-expression and amplification of HER2neu. She completed RT to the lower spine, and in 1/2012 began IT trastuzumab with continuation of capecitabine and lapatinib. There was progressive LMD in 2/2012 prompting escalation of IT trastuzumab dosing and addition of IT topotecan with systemic trastuzumab. In 10/2019, CSF showed rare malignant cells and IT topotecan was switched to cytarabine while continuing IT trastuzumab, now with durable remission ever since. The low LMD burden and aggressive therapeutic approach, including IT trastuzumab, combined with radiation and systemic therapy may explain the exceptional survival.
NIMG-47. A MULTIMODAL DEEP LEARNING MODEL FOR PREDICTING OVERALL SURVIVAL IN GLIOBLASTOMA PATIENTS
Authors: Shahriar Faghani, Mana Moassefi, Gian Marco Conte, Bradley Erickson
Journal: Neuro-Oncology (2022)

Abstract GBMs are highly aggressive tumors, evidenced by their rapid growth. Despite maximal treatment, median overall survival ranges between 16 and 20 months. Several studies use patients' diagnosis time(pre-surgical) imaging to predict their survival, but having a model that can predict the days till death for the patients who received the first standard step treatments (Stupp protocol) and now showing secondary progression signs is highly needed. In this study, we aimed to predict the overall survival of Glioblastoma(GBM) patients by developing a multimodal deep learning model using post-operative magnetic resonance imaging(MRI) and patients' age. We included GBM patients who met the following inclusion criteria: having maximum surgical resection followed by concurrent chemoradiation and showing secondary progression signs in follow-up imaging while being on adjuvant temozolomide treatment. We obtained contrast-enhanced T1(CET1) and T2-weighted(T2W) MRIs at progression time and patients' age and death dates. We calculated the days of survival from the day of the MRI. Dataset was split into train, validation, and test set at the patient level. CET1 and T2W MRIs were skull-stripped and coregistered for each patient. To mitigate data imbalance, we used the deep imbalance regression method for training a 3-D Densenet121 model with the concatenated CET1 and T2W as inputs. One hundred features were extracted from the optimized model and concatenated with the normalized age of each patient; the resulting output vectors were passed through the second dense neural network for final prediction. We included 110 patients who met the inclusion criteria. With the overall survival ranging from 16 to 4500 days, a mean of 582.4 and a standard deviation of 694.3, we achieved the test set's root mean square error of 261 days. Further refinement with more data, including clinical data such as comorbidities and external validation, is required prior to adoption in clinical practice.